The present invention relates to microbially-stable liquid pharmaceutical compositions comprising suspended bismuth-containing pharmaceutical agents and a benzoic acid/sorbic acid preservative system. In particular, it relates to efficacious, microbially-stable, highly palatable liquid bismuth-containing pharmaceutical compositions suitable for oral administration.
Liquid suspensions containing bismuth are well known (e.g., De-Nol sold by Gist-Brocades, N.V.; Pepto-Bismol.RTM. sold by The Procter & Gamble Company). Such compositions are used widely for a variety of gastrointestinal disorders such as diarrhea and nausea and, more recently, have been used for treating C. pylori infections of the gastrointestinal tract. These compositions must be microbially stable, i.e., resistant to growth of bacteria, molds, yeast and fungi, during manufacture and storage. This includes resistance to microbial growth after the consumer has opened the composition's container.
While there are seemingly an unending number of preservative agents known in the literature, one must be concerned about a myriad of factors when deciding on the particular preservative to be used in a composition. Just a few of these considerations are: impact on taste and flavor system, compatibility with the suspension system and color and pharmaceutical agent, stability of the preservative in the particular container, effectiveness of the preservative against the microbial growth possible in the compositions, the pH of the composition, etc., all which can adversely affect the aesthetics and/or effectiveness of the pharmaceutical agent and/or preservative system.
This large number of known preservative agents includes benzoates and sorbates. For example, see: Antimicrobials in Foods (published by Marcel Dekker, Inc., New York; 1983; Branen and Davidson, Editors) Chapters 2 and 6; The Revival of Injured Microbes, The Society for Applied Bacteriology Symposium Series No. 12 (Academic Press, New York; 1984; Andrew and Russell, Editors) pages 302-303; Rushing and Senn, Proc. Fla. State Hortic. Soc., 76, 271 (1963); Beuchat, J. Food Protection, 44(6), 450-454 (1981); and Beuchat, J. Food Science 46 771-777 (1981); the disclosures of all these publications being incorporated herein by reference in their entirety. Pharmaceutical compositions in which benzoates and sorbates are noted as optional components are described in: U.S. Pat. No. 3,927,205, to Ohno et al., issued Dec. 16, 1975; U.S. Pat. No. 4,120,946, to Queuille et al., issued Oct. 17, 1978; U.S. Pat. No. 4,443,433, to Knecht et al., issued Apr. 17, 1984; and U.S. Pat. No. 4,482,542, to Schneider et al., issued Nov. 13, 1984; the disclosures of all these patents being incorporated herein by reference in their entirety.
In spite of the large amount of research aimed at developing efficacious and microbially-stable liquid bismuth-containing compositions, there is a continuing need to provide such compositions which are efficacious and have good aesthetics and good storage stability. It has been discovered that a preservative system comprising low levels of benzoic acid and low levels of sorbic acid is particularly well suited for use in liquid bismuth-containing suspensions. Such a preservative system has several benefits, including: little or no negative impact on product aesthetics (e.g., taste, color, suspension system), preservative effectiveness especially well suited for the pH range encountered over the life of the composition, compatibility of the preservative system with both glass and plastic containers, better preservative activity than either agent alone at these low concentrations, and/or stabilizing effects on the pH of the composition over its life.
It is therefore an object of the present invention to provide microbially-stable bismuth-containing liquid suspensions which are aesthetically acceptable, have good storage stability, and have good preservative activity An object of the present invention is also to provide liquid bismuth-containing compositions which are resistant to microbial contamination and/or growth. A further object is to provide compositions that are believed to have less propensity to change pH over the shelf life of the composition, and to provide effective preservation of the compositions over that pH range. In addition, it is an object to provide such compositions that are compatible with a variety of containers, including glass and plastic bottles.
These and other objects of the present invention will become readily apparent from the detailed description which follows.
All percentages and ratios used herein are by weight unless otherwise specified, and all measurements are made at 25 C unless otherwise specified.